DE2632550A1 - NEW FLUOROUS STEROIDS AND METHOD FOR PRODUCING THEM - Google Patents

Description

ClBA-GEIGY AG, CH-4002 Basel VeLf ^ '"l" Vii

Case 4-10000 Germany

New fluorosteroids and methods of making them

The subject of the present invention is the previously unknown group of compounds of the 11, ^ -unsaturated 9a ~ fluorine steroids, and processes for their manufacture. In particular, the invention relates to the compounds of the general formula I.

(D

st

where St represents the remaining, optionally substituted and / or otherwise modified part of the steroid structure, R is an optionally ketali.sie.rte oxo group, a optionally substitin. ^ ;; th lower alkylidene radical, a

6 G ι, 8 S 6/1 2 1 5

CIB ^ -SEiGYAG

optionally etherified or esterified hydroxyl group with a hydrogen atom or an optionally substituted lower aliphatic hydrocarbon radical, or a hydrogen atom together with an optionally substituted lower alkyl group, and R a lower alkylidene radical _: an optionally acidified or esterified hydroxyl group /; · '* nutmnicn with a hydrogen atom, a Niederalkylres u together with a hydrogen atom, or in particular two Wassersteffatome means ₃ - where instead of one of the ^; named :: v-Ja ^ s ^ r stoff at on.e of the residues R and R a

- ■ χ y

^ ■ '■>_; L "'·' ■ r.'wMt-L.'t-lit-lri'iur ^ lie ·, can, sorie procedure for Eiii: ¹ osition iicicr connection ei.

Dti; The term "lower", wherever it is in context, it ■ ■ in: -m organic residue vc-rhommt, denotes such a ..eist with a maximum of 7, but preferably with 1 to 4 carbon elements.

Dar ί ^ St St besteh "sxis the ring A (carbon atoms CI L-Is C-5 and C-IO), and the remaining carbon atoms οes ring B (C-6 and C-7) and carries the anguläre methyl group (C-J It can also be modified in other ways, for example a structure with enlarged or narrowed rings, such as the A-Ncr- or A-Nor-B-homo structure and / or a Riiigübarbrüclr.uig ₅ rB have the 3λ , 5 -cyelo linkage. The rings A uivü B can with respect to one another.

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Take configuration. The radical St can have one, two or more double bonds, as in the 1,2-; 2,3-; 3,4-; 6.7-; but above all 4.5 or 5.6 positions. Of the The remainder of St can also be replaced by free, etherified and, in particular, esterified hydroxyl groups, e.g. in the 3- and / or 19-, especially in the 3ß-position, by free or ketalized oxo groups, especially in the 3-position, by lower alkyl radicals, e.g. in the 7 a- or especially 6a-position or by halogen atoms, such as bromine or especially chlorine or fluorine atoms, in particular in the 2- and / or especially in the 6a-position, be substituted.

A lower alkyl radical is, for example, an n-propyl-, i -projy-, n-butyl, i-butyl, sec-butyl, tert-butyl, a branched one or preferably straight pentyl, hexyl or heptyl radical, but above all an ethyl or methyl radical. A lower one

aliphatic hydrocarbon radical is a lower alkyl radical, e.g. one of those already mentioned, or a corresponding residue that still has one or two multiple bonds, i.e. double bonds or acetylene linkages, such as a Lower alkenyl, lower alkynyl and allenyl radicals, for example a vinyl, allyl, methallyl, propargyl, hexadiynyl and especially ethynyl radical. A lower alkylidene radical is a den Above-mentioned lower alkyl radicals or lower alkenyl radicals corresponding, at a carbon atom divalent radical, such as an ethylidene or isopropylidene, especially a methylene radical, or a vinylidene radical.

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CIBA-QEIQYAG - 4 -

-The already discussed lower aliphatic hydrocarbon radical and possibly also the lower alkylidene radical can be substituted by * one or more, identical or different substituents ₃ which are mainly in the α- and / or β-position (corresponding to the ■ 20 or 21 Position of steroid cooling). Suitable substituents are Ilalogenatome, for example chlorine and fluorine, optionally etherified and esterified hydroxyl groups, in particular, optionally ketalized oxo groups and optionally esterified carboxyl groups into consideration, the carboxyl groups of _j in the form of their salts, in particular alkali metal salts may be present. The esterified carboxyl group is primarily to be understood as meaning a carboxyl group which is present in the form of its ester, in particular one with lower alkanols,

but also those which have a 6 or in particular with a hydroxyl group which is suitably removed and which occurs as a substituent

5-part lactone ring closes.

A ketalized oxo group is derived in particular from lower alkanols, e.g. from methanol or ethanol, or preferably of cc- or β-lower alkanediols, e.g. 1,2- or 1,3-propanediol or especially ethylene glycol; however, it can also be derived from the corresponding sulfur analogues mentioned "Be derived from alcohols and instead of one or both of the oxygen" atoms Have sulfur atoms.

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CIBA-GEIGY AG

An etherified hydroxyl group is derived in particular from a lower alkanol, preferably a straight-chain, for example methanol, ethanol, propanol and butanol, an aryl-lower alkanol, preferably a phenyl-lower alkanol, for example benzyl alcohol or triphenylmethylcarbinol, or from an oxygen-containing heterocyclic alcohol, e.g. 2-tetrahydropyranol or 2-tetrahydropyranol . It can also be derived formally from a 1-lower alkoxy-lower alkanol, for example L-butoxyethanol; the 1-butoxyethoxy group is to be mentioned as an example of such a etherified hydroxyl group. An etherified hydroxyl group is to be regarded as such as it is in an acetalized> betw. ketalized vicinal steroid diol, e.g. 16a, 17a-diol, orlage. The non-steroidal component which always binds two such vicinal etherified hydroxyl groups is preferably a lower aliphatic, cycloaliphatic or arylaliphatic ketone, for example acetone, cyclopentanone, cyclohexanone, acetophenone or benzophenone, or an aldehyde. : .B. Formaldehyde. A special case of the etherified hydroxyl groups is also 17a, 20; 20,21-bismethylenedioxy; grouping should be mentioned.

An esterified hydroxyl group is derived in particular from an inorganic oxygen-containing acid, for example one of the sulfuric or phosphoric acids, or preferably from an organic s;.,: Re, for example a sulfonic acid, for example an aronuit i rsr'.c ■; Sulphonic acids such as benzene, toluene or

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CIEA-CEäGYAG

ρ-bromobenzenesulfonic acid, or an alkanesulfonic acid, such as Met! '- ansulfonic acid, or in particular of a carboxylic acid. Ais ~ -ί.η ■■ -. esterified hydroxyl group is also a lactonized one IT "d: j>:", group to consider. His education and conscience SubfctituLionsreaktionen after is; also a halogen atom, in particular van., fay t-ich is in the 21-position, e.g. the iodine, bromine Insi> esonde "3 chlorine or fluorine atom, as a special, abei irli; epitome of the case of a strong acid

. .-j ι: v--. ·. ι: en hydroxyl group, ie one by the iodine, bromine, GaIv- ' ^: L - :: - w. F If-or-hydrogen acid esterified hydroxyl group,

As l-arb ^ r ^ -acid comp ^^ ants of an esterified hydroxyl,: - _t , '- _: r: .in;. -r.>;: -; r line c's usual in steroid chemistry ί rsn, a. ^ eh In Γοπη der .-. ^ speaking orthocarboxylic acids,

bt, b: sometimes monocarboxylic acids with a maximum of 18 carbons:.; c ·. :. tomer: _f v'ie aliphatic ζ carboxylic acids or orthocarboxylic acids, i τ ■■ -.- ■ : -dare c 'c , A η' ^. i ;; en acid, 0_ ühoauiei sen acid or a "."" ^? .« -. [βϊ., -. ■ .i -.- än-.carbcp.s' - "VJt-; or, - ':, rhocarboxylic acid, its lower; . - "Xr- - ■ / ■ [. One -v ^ r just mentioned -. ■ -. :: is, primarily the Z -w: .. ic - _{:, - r} Butter-- Iscbutter-, Valerian- , Isovalerian-, Oen-ni :. » and dimethyl acetic acid and especially the caproic,

"i ^: .."! - ■■ £ t! r / less igic and acetic acid; but also corresponding halogenated _ .; ei .Ikancarbo-iAäuren, such as chloroacetic acid, trichloro or

_..::: £ Ovvi & Tues: -: '' i \ ■■!> - -essi ^ i. "'.. .ipryl, pelargon, capric,;.: wiy> - ■ j M3 "ris_Ln- _s Palmitir: - ...-" oi stearic acid, the undecyl- 1; . ~ LJ. üi>c; ecyleii3iiaren, the elaicin = and oleic acid; cycloaliphatic

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INSPECTED

CIBA-GEIGYAG - 7 -

or cycloaliphatic-aliphatic monocarboxylic acids, e.g. the cyclopropane, cyclobutanoic, cyclopentanoic and cyclohexane carboxylic acids or the cyclopropyl or cyclobutyl methane carboxylic acid and a cyclopentyl or cyclohexyl ethane carboxylic acid; aromatic carboxylic acids, e.g. optionally by fluorine, chlorine, bromine, hydroxy, lower alkoxy, lower alkyl or Benzoic acids or orthobenzoic acids substituted by nitro groups; Aryl- or aryloxy-lower alkanecarboxylic acids and their in chain-unsaturated analogs, e.g., optionally, such as given above for benzoic acid, substituted phenylacetic or phenoxyacetic acids, phenylpropionic acids and cinnamic acids; and heterocyclic acids, e.g. furan-2-carboxylic acid, 5-tert-butylfuran-2-carboxylic acid, 5-bromofuran-2-carboxylic acid, thiophene-2-carboxylic acid, nicotinic or isonicotinic acid, 3- (4-pyridyl) - propionic acid, if necessary by lower alkyl radicals substituted pyrrole-2- or -3-carboxylic acids, but also Corresponding dicarboxylic acids with a maximum of 12 carbon atoms, e.g. succinic, glutaric, adipic and phthalic acid as well corresponding a-amino acids, in particular a-amino-lower alkanecarboxylic acids, preferably those of the naturally occurring configuration, e.g. glycine, proline, leucine, valine, Tyrosine, histidine, asparagine, as well as glutamic and aspartic acid.

In a favorable location, e.g. if they are separated from one another by two or three carbon atoms, you can two hydroxyl groups with one molecule of an orthocarboxylic acid

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CIBA-GEIGYAG - B -

. Form cyclic esters, as in particular in the case of Orthoesters? Iiederaliphatic ortho-acids with 17a, 21-

-Dib dro / pregnan connections. The third oxygen atom the ürthosäurefunktion is usually through the remainder of a lower alkanol, especially methyl or ethyl, occupied. In an analogous manner, orthoesters of orthocarbonic acid with 17a, 21-dihydroxypregnane compounds are also used gestalte.:· in this case carries the central carbon atom two lower alkoxy groups.

The novel 11,12-unsaturated 9a-fluorotheroids according to the invention can be used as intermediate products for the synthesis of valuable pharmaceutical active ingredients, in particular for horir therapy and for controlling fertility, -3 ZuA-uLz, LLi PuLb-biitiiLLtila. Several of them, ζ, Έ>. the compounds highlighted below are at the same time biological in themselves

Effectiveness and can therefore directly as

Active ingredients are used in the above-mentioned areas of application.

The 11, ^ - unsaturated 9a according to the invention -Fluorosteroids are chemically novel general Process available, which is characterized in that a 9a-fluoro-11ß-hydroxy-steroid, preferably with temporary protection of any carboxyl and hydroxyl groups that may be present, with a compound of

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CIBA-GEIGYAG

Formula F ~ SX where X is one derived from a secondary amine Amino group means, converts.

Compounds of the general formula are preferred as starting materials

(II)

in which St ₅ R and R have the meanings given above, _s where the remaining hydroxyl and carboxyl groups which may be present are preferably in esterified form. If desired, the products obtained are im

Framework of the end products of the formula I into one another in itself converted in a known manner by, for example, protected functional groups, such as primarily esterified carboxyl groups and esterified hydroxyl groups or from the 17a, 20; 20,21-bismethylenedioxy grouping the dihydroxyacetone side chain. Also others in steroid chemistry common conversions can be performed; in particular, hydroxyl groups can be esterified or etherified, eliminated or are oxidized to oxo groups, oxo groups are ketalized,

or to hydroxyl group ·! s optionally with simultaneous Introduction of a hydrocarbon residue, reduced

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CiBA-GEIGYAG - IO -

χ -? '31; Ctßn and / cder further double bonds in the obtained Connections are introduced. These subsequent conversions can be carried out individually or as appropriate Perform coordination.

The process according to the invention is quite surprising, because the reactant of the formula F-SX used has so far only served for the purpose of fluorination by replacing a "sweetener" function with fluorine, cf. LN Markovskij, \ .E = Pashissnik and AV Kirsanov: Synthesis 1973 (December), 787-789. Also surprising is the formation of the 11,12-TiCi- ski bond by cleavage of an 11-position hydroxyl- ['- "'' C ₅ which is only an exceptional case, see C. Djerassi: t'C: .id Reactions, pp. 227-26o and the literature cited there. .-it, and only for distantly related connections ■ 3c was rushed.

The method according to the invention runs smoothly ■: xici! under very mild reaction conditions, so that ^other: irr lonelle groups remain mostly intact. It is recommended that any carboxyl groups present in the starting materials of the formula II should be present in an esterified form in order to prevent the conversion into an acid fluoride

to be protected.

Also any hydroxyl groups present, r'J? -Ι taken dr'.e too reactive? !! / ^ - hydroxyl group, should be used in starting materials of formula II during the conversion into

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CLBA-GEIGY AG - 11 -

in a protected, such as etherified or, preferably, esterified form. Easily hydrolyzable etherified hydroxyl group *, eg tetrahydropyranyloxy groups, as well as ketalized oxo groups. can be cleaved hydrolytically to free hydroxyl groups or oxo groups in the course of the dehydration reaction or the processing of the reaction mixture. To adequately protect the dihydroxyacetone side chain, however, it is sufficient for one of the two hydroxyl groups to be esterified by a carboxylic acid containing at least three carbon atoms, such as one of the abovementioned, especially propionic, butyric or trimethylacetic acid. A protecting group from such a large enough already, that is, the reagent of the two hydroxyl groups of the esterified _n both as the free to keep. Of course, the dihydroxyacetone side chain can be present as a 17a, 20; 20 / 11- bismethylenedioxy group (the term "dihydroxyacetone side chain" means the 17a, 21-dihydro: ^ «-20-oxo-pregnane group. ) The groups mentioned can subsequently be converted into the desired free groups in a known manner, for example by hydrolysis.

The reactant (dehydrating agent) of the formula FoSX is a disubstituted aminosulfur trifluoride, i.e. » one in which the nitrogen atom to the sulfur atom and

two carbon atoms is bonded. The substituents of the amino group are accordingly two identical or different open-chain or carbocyclic, optionally aromatic ₃ hydrocarbon radicals, in particular lower alkyl radicals, for example

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the above-mentioned or phenyl radicals, it being possible for the two radicals to be linked together by a simple GC bond, by an oxygen bridge, or by a lower-alkylated nitrogen atom. Preferred as the amino group denoted by X is a di-lower alkylamino group or lower alkylphenylamino group, such as dimethylamino, methylethylamino, methylpropylamino, methylphenylamino, ethylpropylamino, ethylphenyl amino, dipropylamino, diisopropylamino, or dibutylamino group, or an optionally C- ^{lower alkylated pyrrolidino, piperidino, morpholine or N'-lower alkylpiperazino group, such as N 1} -ileth3 "lpiperazino group, with synsnetric amino groups Above all, this amino group is the diethylamino group and the corresponding fluorinating agent is diethylaminosulfur trifluoride. '. - - "■"".'

The inventive implementation is optionally in the presence of inert solvents or mixtures thereof carried out. The reaction temperature depends on the specific properties of each reaction mixture, in general it ranges between -20 ° to 80 °, preferably between 0 ° to 30 °; it is advantageous to work at room temperature.

The inert solvents used are those which under the reaction conditions used neither with the Reactants still react irreversibly with the products. The following solvents are particularly suitable: carbocyclic hydrocarbons, e.g. saturated carbocyclic

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Hydrocarbons, such as cyclopentane, cyclohexane, cycloheptane, decahydronaphthalene, or aromatic carbocyclic hydrocarbons, such as benzene, toluene or xylenes, which can also be halogenated on the core, such as chlorobenzene, dichlorobenzenes, Bromobenzene or fluorobenzene, and especially aliphatic saturated hydrocarbons, preferably those that are Atmospheric pressure and room temperature are liquid, such as pentanes, Hexanes, heptanes, octanes, or those that are halogenated, especially chlorinated, such as chloroform, 1,1- or 1,2-dichloroethane, ' 1,1-, 1,2- or 1,3-dichloropropane, and especially dichloromethane. Aliphatic and especially cyclic ethers, such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, also come into consideration. Tetrahydrofuran and especially dioxane, and nitrogen-containing aromatic heterocyclic compounds, such as Pyridine and its homologues or quinoline. If necessary, an excess of fluorinating agent can be used as a solvent use, and / or combine several of the solvents mentioned.

The subsequent release of the protected oxygen-containing functional groups in the process products obtained takes place in a manner known per se, preferably by hydrolysis. Etherified hydroxyl groups are hydrolyzed preferably under the conditions of acid catalysis in the presence of an inorganic acid, e.g. sulfuric acid or a hydrohalic acid such as der.Chlor- ₉ bromic or hydroiodic acid, or an organic acid, e.g. a sulphonic acid,

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such as p-toluenesulfonic acid or sulphosalicylic acid, or a stronger carboxylic acid such as oxalic acid or formic acid. Similarly, enol ethers and ketals or acetals are also hydrolyzed to corresponding (b-cc derivatives. Carbonyl-containing ester groups of various types, be it esterified hydroxyl groups, esterified carboxyl groups, enolacylated oxo groups or lactone groups, k ^? Ir-t ;;. R. Hydrolyzed under acidic conditions are preferably produced, however, they hydrolyzed under base catalysis basic catalysts used are preferably hydroxides, carbonates or Eydrogencarbonate the alkali metals, especially of sodium ny: - 'T'aliuin ?. By a suitable choice of the Reaktionsinittel and "■ - ■..: · .: ~ .j; n ~ s to kaaλ also known to selectively single Hydroxylprii-: i release _s example of both in a 17a, 21-Orthoester.

-;: .- ■ only release the 21-position hydroxyl groups, whereby • it "? 7a-hour remains as a normal esterified hydroxyl group - es': u'-en . Esterified hydroxyl groups can also be reductively: re.. tL?: en, ε. Γ. by the action of an ester reduction with · .. ..Is j such as a complex hydride or diborane.

The subsequent esterification or etherification of t ^: y ^ ~~ -iTlgruppei: in the compounds obtained it is more likely that :; ^r aIls in a manner known per se. For the purpose of esterification, the compound to be esterified is retained, for example, with excess acid itself, such as with formic acid, or with ^: .. * .- ..: -; reactive derivative thereof, for example with a derivative of a oer ban specified acids, in particular with an anhydride or halide Shuic ₅ advantageously in the presence of a tertiary base,

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ORJGiNAL INSPECTEO

CiBA-GEiGYAG - 15 -

ες

such as pyridine, quinoline or N-ethyl-piperidine. Hydroxyl groups which are difficult to esterify, for example a tertiary 17α-hydroxyl group, can advantageously be esterified with an acid anhydride under the catalytic action of organic sulphonic acids, for example benzene, p-toluene, salicylic or camphor sulphonic acid. To form orthoesters, in particular those derived from 17a, 21-dihydroxy compounds, one works in a known manner under the conditions of transesterification, for example so that the suitable compound with free dihydroxyacetone side chain with excess desired orthocarboxylic acid ester, for example triethyl orthopropionate, in Treated in the presence of a strong acid. Advantageously, max * takes care of the removal of the volatile lower alkanol released.

For etherification, for example, the compounds to be etherified are treated with reactive derivatives of Alcohols, e.g. with esters of strong acids, such as halides, sulfates or sulphonic acid esters, with the Aikoho! Component in particular one of the abovementioned alcohols comes into consideration. The reaction is preferably carried out in the presence of basic Means through. For the formation of tetrahydropyranyl ethers and analogous ethers, an appropriate reagent is preferably used unsaturated derivative such as 2,3-dihydropyran or a vinyl lower alkyl ether, e.g. vinyl butyl ether, and carries out the implementation under acid catalysis conditions, preferably in the presence an organic sulphonic acid.

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The optionally to be carried out esterification of Carboxyl groups also take place in a manner known per se. For example, the carboxylic acid to be esterified is treated with excess! :: an alcohol, especially one of the above, in the presence of an acidic catalyst, e.g. a strong inorganic acid, or the free acid is first introduced into their reactive derivative via, such as chloride or anhydride. and converts this with the desired alcohol. Lower alkyl ester, especially methyl esters, can also be advantageously produced by the free carboxylic acid to be esterified with the corresponding one Diazonicderalkan, especially diazomethane, converts. The lactonization of a carboxyl group usually occurs spontaneously. the release of a carboxyl group present as a salt

by acidification; the lactonization can also be achieved by acid catalysis and / or use of dehydrating agents such as acetic anhydride, anhydrous copper sulfate, molecular sieves, or by azeotropic distillation.

^{The ketalization, enol ac3 '-} lation and formation of enol ethers, which may be carried out, in particular to protect the oxo groups, also takes place in a manner known per se, in particular under the conditions of acid catalysis and optionally with the use of dehydrating agents or azeotropic distillation. For ketalization, for example, lower alkanols, such as methanoi or ethahol, and in particular α- and / 3-glycols, such as 1,2- or 1,3-prcpanediol and 1,2- or 2,3-butar-diol, and above all, are used

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Ethylene glycol, or reactive derivatives of these alcohols, such as acetals or ketals, especially those in which the carbonyl component is highly volatile, such as 2,2-dimethyl-l, 3-dioxolane. In an analogous manner, but starting from the sulfur analogues of the alcohols mentioned above, especially from 1,2-ethanedithiol or a reactive derivative, analogous thioketals are obtained.

In an analogous manner, vicinal steroid diols are reacted with non-steroidal ketones or aldehydes, as e.g. in the formation of ketals, e.g. acetonides, or acetals of 16a, 17ct-diols, or in the conversion of 17tx, 21-dihydroxy-20-oxo-pregnanes with formaldehyde to give corresponding 17a, 20; 20, 21- -Bismethylendioxy-Derivacen is the case. Instead of a free 16,17-diol, it is also possible to use a corresponding ester, in particular a 16-monoester, use; the intermediate release of the Diol then happens under the reaction conditions of ketalization or acetalization, with the addition of a lower alkanol to the Reaction mixture facilitates this release. Instead of the free Carbony! Compound can also be a reactive derivative of it, e.g. an acetal bzx ?. Kstal, derived from a volatile Alkanol, in particular methanol or ethanol, or an enol acetate, for example an enol acetate such as isopropylidene acetate, or a mixture of the free ketone and such a derivative thereof use. In the case of aldehydes, their oligomers also come into play, e.g. 'Primers such as paracetaldehyde can be considered. For the formation of the enol ethers the reagent used is preferably an orthoester

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CIBA-GEiGYAG - IR -

Lower alkanol, in particular methanol or ethanol, with a lower aliphatic carboxylic acid, especially the

Formic acid; particularly preferred reagents are methyl orthoformate and especially ethyl orthoformate. In the presence of However, dihydroxyacetone side chain is the possibility of one simultaneous formation of the 17ct, 21 orthoesters must be taken into account. The enol acylation is advantageously carried out by reaction with a reactive derivative of the desired carboxylic acid Acid catalysis by; preferably an anhydride such as acetic anhydride is used as the reagent and an organic acid such as Benzene *, p-toluene, salicylic or camphor sulphonic acid, as catalyst. Ais reactive carboxylic acid derivatives can one - also use ketenes, especially the unsubstituted ketene. Γ'ϊσι lalle one with a double bond conjugated oxo group can the ketal, enol ether or enol ester formation from a shift of the double bonds, e.g. in the case of the 3-0 :: o- Δ'_ grouping, the 4,5 double bond migrates to the 5, 6-position. In the process products obtained, free hydroxyl groups can also be oxidized to oxo groups in a manner known per se. The preferred oxidizing agents for secondary hydroxyl groups are compounds of hexavalent chromium, such as chromium trioxide, Chrome saturates and theirs. Alkali metal salts, one being used as the reaction medium advantageously lower alkanecarboxylic acids, such as acetic or propionic acid, or pyridine or acetone, optionally under Dilution with a halogenated lower alkane such as dichloromethane

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CLBA-GEIGY AG - 19 -

or chloroform, and / or used in the presence of aqueous sulfuric acid. In an analogous way, the primary 19-hydroxyl group is oxidized; under milder reaction conditions, the 10- -Carboxaldehyde group, or, if the reaction is carried out vigorously, the 10-carboxyl group. Another preferred alternative of oxidation A secondary hydroxyl group is the Oppenauer oxidation, i.e. the oxidation with a ketone such as acetone or cyclohexanone the catalytic influence of an aluminum lower alkoxide, such as Aluminum isopropylate. An al IyI is marriage, i.e. one next to one Double bonded hydroxyl group, such as the hydroxyl group of a 3ß-hydroxy-4-ene compound, can in a manner known per se are oxidized by manganese dioxide to the corresponding oxo group. This smooth implementation is especially beneficial when you have a α, ρ-unsaturated oxo group is intended to regenerate during the reduction another oxo group was also reduced.

The primary 21-hydroxyl group can also be found in an oxidize themselves to the oxo group in a known manner, for example, with atmospheric oxygen in the presence of a copper (II) salt, such as

Copper acetate. You can also proceed indirectly by ^{treating a 21-H3 T} hydroxy compound with tosyl chloride (or an equivalent sulfenic acid derivative in pyridine or a similar tertiary base, the intermediate of the partial formula

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CIEA-6E! GYAQ

with nitrosodimeühylaniline to a nitrone dt-r sub-formula

ü -CH

condensed and this hydrolyzed with water under acid catalysis. A special case of the formation of the 21-aldehyde group is acid-catalyzed rearrangement of the dihydroxyacetone side chain into the 17-unsubstituted 20,21-dioxo-pregnane group. Depending on solvent used (e.g. water, an alkanol or alkanediol or a carboxylic acid) the terminal aldehyde group is obtained as hydrate, hemiacetal, acetal or Ac3'lal, or a tauthorized form of it. A 21-position hydroxyl group the dihydroxyacetone side chain can also be eliminated in a manner known per se by converting it into one with a strong acid esterified hydroxyl group and this reductively, e.g. with Z-ink in acetic acid, sodium bisulfite, or preferably sodium iodide removed in acetic acid. Suitable ester-forming strong acids are organic sulfonic acids, especially toluene and very specifically Methanesulphonic acid and hydrohalic acids, in particular To mention bromic and especially hydroiodic acid. The elimination of a 21-iodide with sodium bisulf is particularly advantageous it in ethanol.

In the process products obtained can also be oxo groups, in particular the 3-oxo group and especially the 17-oxo group, reduce to hydroxyl groups. The reduction is carried out in a manner known per se; advantageous

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one uses diborane or complex hydrides, especially those of aluminum or boron with an alkali or alkaline earth metal, such as sodium aluminum hydride, calcium borohydride, lithium borohydride, but in particular lithium aluminum hydride and especially sodium borohydride, or its derivatives, in which one or more hydrogen atoms are replaced by lower alkoxy radicals, such as methoxysodium borohydride and in particular Tri-tert-butoxylithium aluminum hydride. The choice of solvent and the reduction conditions depend on the reducing agent used and correspond to generally known principles. In the case of a selective reduction, e.g. that of the 17-oxo group, the other oxo groups are temporarily protected as ketals or enol esters or enol ethers, in the case of the presence of one

/ 4
3-0χο ~ / Λ grouping ;; one can also proceed in such a way that one reduces this initiation and then selectively, for example with manganese dioxide, back

4th

dehydrated to the 3-Οχο-Δ grouping.

The reduction of the oxo groups, especially the 17-oxo group, can also be carried out in a manner known _{per se with the simultaneous introduction of a hydrocarbon radical, in particular a lower aliphatic hydrocarbon radical,} for example one of those mentioned above, by reacting a corresponding oxo compound with a corresponding organometal compound . If the hydrocarbon radical to be introduced is a lower alkyl radical, the preferred organometallic compound is a Grignard compound, for example a lower alkyl magnesium halide, such as methylmagnesium bromide or iodide, or non-alkyl lithium, such as methyllithium; \ 7enn a 1-alkynyl radical, in particular the Aethin} ^r lrest, einzu-

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C5BA-GE1GY AG % s

lead, it is advantageous to use a corresponding alkali metal compound, for example sodium or potassium acetylide or, in particular, lithium acetylide. In the latter case, it is particularly advantageous to use the lithium acetylide in the form of its complex with ethylenediamine. The other oxo groups must in these reactions in an analogous manner to how. described above for the selective reduction. If the oxo group to be converted is combined with one or two adjacent toppal bonds to form a conjugated system, as is the case, for example, with the 3-oxo-4,6-diene group, then one can use the known method, especially in the presence of a Kupier ( I) -salt 5 the reaction with a * Grignard compound,: .nsi .especial a methylinagnesium halide, lead in such a way that the -..--! Leading hydrocarbon radical is not on the carbon atom bearing the oxo group, but on the one at the end of the conjugated Sysiiiiris standing carbon atom is introduced, which corresponds formally to a 1,4- or 1,6-addition. The oxo group is converted to the hydroxyl group. which, however, is then in an enol group and rearranges during work-up to form an oxo group with formal saturation of the cC double bond. the end

the conjugated system given above as an example results then the 7a-methyl ~ 3-oxo ~ 4-ene group.

Double bonds can likewise be introduced into the end products obtained in a generally known manner. Can be Z ". E. / Λ -3 ~ 0xoverbindungen, optionally in the form of its 3-Enolac3 ^r late or 3-enol ethers with Chir.onGn as Chlorani.1

6098H6 / 12 15

or in particular 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, implement, thereby depending on the choice of the known per se Reaction conditions the 6,7 and / or 1,2 double bond arises.

The 1,2-dehydrogenation of Δ -3-ketones can also in a known manner by treatment with selenium dioxide ₅ or microbiologically, for example by means of the microorganisms Corynebacterium simplex, or Septomyxa affinis, achieve; 6,7-dehydrogenation is also achieved by reacting an enol ether of a Δ -3-ketone with manganese dioxide.

Among the 11,12-unsaturated 9a- -Fluorosteroids are of particular interest because of their beneficial biological properties Formula IA

CTL OR,

(IA)

vj or in

R-, the oxo group, a hydrogen atom together with an esterified one or free hydroxyl group, or two hydrogen atoms, R "one Hydrogen atom or the methyl group, R "a hydrogen atom or together with the oxygen atom, in particular through a lower alkanol or a cycloaliphatic alcohol, such as cyclopentanol o'der Cyclohexanol, etherified or by a carboxylic acid, preferably

609886/1215

ciba-geigyag _ 24 -

wise an aliphatic carboxylic acid with 2 to 12 carbon atoms, esterified hydroxyl group, and R, a hydrogen atom or a lower aliphatic hydrocarbon radical, or R- and R, together stand for a valence stroke, with 1,2- and / or 6,7 in the positions - there may be an additional double bond each. These compounds are distinguished in particular by their pharmacological properties similar to those of sex hormones. On the one hand, they are centrally effective by blocking the excretion of pituitary gonadotrophins; on the other hand, they also affect both male and female sexual functions peripherally, as can be demonstrated in current animal experiments. Accordingly, they have very valuable anabolic, androgenic, progestative, antiandrogenic, antibestrogenic, ovulation-inhibiting and gonad-inhibiting activities. They are of interest as contraceptives because of their peripheral fertility-inhibiting properties, for example their contraceptive influence on egg transport and / or cervical mucus, and their antinidation activity. Because of these favorable pharmacological properties, they can be used instead of the known sex hormones in corresponding specific. '- ·. Indications apply and are administered for this purpose in the same manner as these, the dosage being determined with regard to the relative effectiveness. In addition, these compounds can be used as intermediates for other compounds of the same Endstorfgruppe, but with modified

6098 8 6/1215 "

CLBA-GE'GY AG - 25 -

pharmacological properties, serve, or as valuable Starting substances for other classes of compounds can be used.

Among the compounds of this group, because of their androgenic-anabolic, but also anti-oestrogenic, antigestagenic and gonadotrophin-inhibiting properties, those compounds of the general formula IA in which R _{1 is} an oxo group, R_ is a hydrogen atom and especially the methyl radical, R "Is a hydrogen atom, a lower alkyl, a cycloalkyl with 5 or 6 ring members or an alkanoyl with 2 to 12 carbon atoms, and R is a hydrogen atom or the methyl radical, and which can also have a double bond in the 1,2-position. However, those compounds of the general formula IA in which R _{1 has} two hydrogen atoms, a hydrogen atom together with a free hydroxyl group, or in particular an oxo group, R «is a hydrogen atom, Ro is a lower alkanoyl or, in particular, a hydrogen atom, also deserve special attention , is an unsaturated hydrocarbon radical with 1-4 C- atoms, in particular the ethynyl radical, and which can also carry a double bond in the 1,2- and / or in particular in the 6,7-position. These compounds are also distinguished by their blocking effect on the release of the gonadotrophins, but above all by their gestagenic, antiestrogenic, antiandrogenic and nidation-inhibiting effect.

¹ O '

Compounds of the general formula IA are by the general dehydrogenation process according to the invention from the corresponding

609886/1215

CiBA-GEfGYAG

llß-hydroxy compounds accessible, provided that Gege- ^; any hydroxyl groups present in the 3- and 17-positions in

are in a protected form. If desired, the hydroxyl groups are subsequently released, or free hydroxyl groups are formed by subsequent reduction, preferably with a complex hydride, from corresponding oxo groups in a manner known per se. If desired, the hydrocarbon radical R 1 can also be introduced subsequently: this starts with compounds of the formula IA in which Ro and R together represent a valence stroke, and the operation is preferably carried out under the conditions described at the outset. If desired, the lower alkyl radical in the 7 <x position can also be introduced subsequently. If a compound of the formula IA ₃ which is unsaturated in the 1,2 and / or 6,7 position is desired, the desired double bonds can also subsequently be converted into a corresponding one Introduce saturated compound in these positions in a manner known per se.

Compounds of the general formula IB are also of particular interest

(IB)

^R 7

609886/1215
ORfGINAt INSPECTED

CIBA-G EIGY AG _ΟΊ

wherein R ₁ - is a hydrogen atom, an α-oriented methyl radical or, if the 1,2-double bond is present, a chlorine atom, R, an oxo group or a hydrogen atom together with an optionally esterified hydroxyl group, R _{7 is} a hydrogen atom, the methyl radical or a Halogen atom, R "two hydrogen atoms, the methylene radical, one hydrogen atom together with an α- or α-oriented methyl radical or an α-oriented free hydroxyl group, Rq a hydrogen atom or an optionally esterified hydroxyl group, and

Rj "is two hydrogen atoms, an optionally hydrated or acetalized oxo group, or a hydrogen atom together with an optionally esterified or etherified hydroxyl group, and in which a double bond can be present in each of the positions 1, 2 and / or 6, 7, and in which the optionally present 16a, 17a-diol grouping is replaced by an oxo compound of the formula R, ..- CO-R.,, · ,, in which R ₁₁ and R, ~ independently of one another are a hydrogen atom, a lower alkyl, phenyl or benzyl radical or together form the tetramethylene or pentamethylene radical, can be ketalized or acetalized. These compounds are distinguished by valuable hormone-like properties and can therefore be used instead of the natural hormones or their known analogs for appropriate specific indications.

Particularly valuable as analogues of the hormones of the adrenal cortex

609886/1215

CLBA-GElGY AG - 28 -

are those compounds of the general formula IB in which R ₁ . a hydrogen atom or, if the 1,2-double bond is present, a chlorine atom, R-- an oxo group, R ₇ a hydrogen atom, a methyl radical and especially a fluorine atom, R ₀ two water

Substance atoms or a hydrogen together with an α-hydroxyl group or a β- or in particular α-methyl radical, Rq and R- 'are each independently a free or an esterified, in particular one esterified by a lower alkanecarboxylic acid hydroxyl group, and in which preferably the 1 , 2 double bond is present. Also preferred are the 16,17-ketals, in particular acetonides, cyclopentanonides, cyclohexanonides and acetophenides of those compounds already highlighted which each have a hydroxyl group in the 16a and 17a positions. Preference is also given to the compounds of the formula IB in which R 1 -, _{R 1:, R 7 and R 1 have the preferred meanings already given, R 1 is} hydrogen together with the methyl group in the α position and R _{0 is} hydrogen. These compounds have a hormonal activity which is analogous to the characteristic properties of the natural hormones of the adrenal cortex; therapeutic

The mineralocorticoid properties, ie the influence on the balance of sodium, potassium and water in body tissues, and above all the anti-inflammatory effectiveness are particularly valuable. Typical representatives of these preferred compounds are 9a-fluoro-17a, 21-dihydroxypregna-4, ll-diene--3, 20-dione, 9a-fluoro-17a, 21-dih} ^r droxy-16a-meth3 ^ 1-pregna -4, ll-di'en- -3,20-dione,

6 0 9 8 8 6/1215

ciBA-GEiGYAG - 29 -

9a-fluoro-17a, 21-dihydroxy-16ß-methyl-pregna-4, ll-diene-3,20-dione, 6α, 9a-difluoro-17a, 21-dihydroxy-pregna ~ 4, ll-diene-3,20-dione, 6α, 9a-difluoro-17a, 21-dihydroxy-16a-methyl-pregna-4, ll-diene-3,20-dione, 6α, 9a-difluoro-17a, 21-dihydroxy-16/3-methyl-pregna-4, ll-diene-3,20-dione, 9α-fluoro-17α, 21-dihydroxy-6α-ynethyl-pregna-4, ll-diene-3,20-dione, 9a-fluoro-17a, 21-dihydroxy-6a, 16a-dimethyl-pregna-4,11-diene-3,20-dione, 9a-fluoro-17a, 21-dihydroxy-6a, 16ß-dimethyl-pregna-4, ll-diene-3,20-dione, and their 21- and / or 17-esters, in particular esters with lower alkane carbon acids, especially acetic, butyric, valeric and trimethyl acetic acid; further

9a-fluoro-17a, 21-dihydroxy-pregna-l, 4, ll-triene-3,20rdione, 9a-fluoro-17a, 21-dihydroxy-16a-methyl-pregna-l, 4, ll-triene-3, 20-dione, 9a-fluoro _r l7a, 21-dihydroxy-16ß-methyl-pregna-l, 4, ll-triene-3,20-dione, 6a, 9a-difluoro-17a, 21-dihydroxy-pregna-1, 4,11-triene-3,20-dione, 6a, 9a-difluoro-17a, 21-dihydroxy-16a-methyl-pregna-1,4, ll-triene-3,20-dione 6a, 9a-difluoro-r17a , 2l! -Dihydroxy-16ß-methyl-pregna-l, 4, ll-triene-3,20-dior:

9a-fluoro-17a, 21-dihydroxy-6a-methyl-pregna-l, 4, ll-triene-3,20-dione, 9a-fluoro-17a, 21-dihydroxy-6a, 16a-dimethyl-pregna-1,4, ll-triene-3,20-dione 9a-fluoro-17a, 21-dihydroxy-6a, 16β-dimethyl-pregna-1,4,11-triene-3,20-dione

and in particular the corresponding 2-chloro analogues and 21- and / or 17-esters of all these compounds, in particular esters with lower alkanecarboxylic acids, especially the vinegar, propionic, butter, valerian and trimethylacetic acid, but also · -

9a-fluoro ~ 21-hydroxy-16a-methyl-pregna-4, ll-diene-3,20-dione, 9a-fluoro-21-hydroxy-16a-raethyl-pregna-1,4, ll-triene-3, 20-dione, 9a-fluoro-21-hydroxy-6a _; 16a-diinethyl-pregna-4, 11-diene-3, 20-dione,

609886/1215

'^ b ORIGINAL INSPECTED

CIBA-GEIGYAG - 30 -

9α-fluoro-21-hydroxy-6α, 16α-dimethyl-pregna-1,4, ll-triene-3,20-dione, 6α, 9α-Difluoro-21-hydroxy-16α-Inethyl-pregna-4, ll-diene-3,20-dione, 6a, 9a-difluoro-21-hydroxy-16a-methyl-pregna-l, 4, ll-triene-3,20-dione, and 21-esters of these compounds, preferably the preferred esters mentioned immediately above, and 9oc-fluoro-16a, 17a, 21- -trihydroxy-pregna-1,4,11-triene-3,20-dione and its 21-ester, preferably the preferred esters mentioned immediately above, and 16,17-ketals, in particular acetonides, acetophenides, cyclopentanonides and cyclohexanonides of the latter compounds.

^T nter the compounds of general formula IB also is of particular importance to the compounds wherein R ₅ is a hydrogen atom, Rr is an oxo group, R ₇ is a chlorine or a fluorine _atom} Rp is a methyl group, or especially two hydrogen atoms, Rq is a hydrogen atom or a free or esterified hydroxyl group, in particular a hydroxyl group esterified with a lower alkanecarboxylic acid, and R-. _{Q stands} for two hydrogen atoms, and in which preferably in the 1,2- and / or in particular

a double bond can be present in the 6.7 pitch. These compounds are notable for their sex hormone-like properties Properties, in particular due to the gestagenic, antiestrogenic, antiandrogenic, as well as ovulation and nidation-inhibiting properties;

they can therefore be used wherever progestins are used ■ 'i.e. Progesterone-like hormones) as pharmaceutical preparations or Contraceptiva used.

The advantageous biological properties of the erfindungsgeraässen Compounds can also be demonstrated using the following examples of some typical active ingredients:

602386/1215

ciBA-GEiGYAG - 31 -

9a-fluoro-17a, 21-dihydroxy-16a-methyl-pregna-l, 4, ll-triene- -3,20-dione 17,21-dipropionate a local anti-inflammatory Effect on, as shown in the cotton granuloma test (rat) in Doses 0.3 mg per pellet shows. Also the 16-epimeric compound, the 9a-fluoro-17a, 21-dihydroxy-16ß-ynethyl-pregnal, 4, ll-triene-3,20-dione 17-valerate-21-propionate, has such an activity in the same order of magnitude. One particularly excellent effectiveness can be achieved with 6a, 9a- -Difluor- ^ a ^ l-dihydroxy-löa-methyl-pregna-l, 4, ll-triene-3,20- -dione 17,21-dipropionate as in 6a, 9a-difluoro-21-hydroxy-16a, 17a-isopropylidenedioxy-pregna-1,4, ll-triene-3,20-dione 21-acetate to be established; develop in the cotton grannloma test (rat) the two compounds have a marked local anti-inflammatory effect over the full dose range of 0.03 to 0.3 mg per pellet. The systemic effectiveness of these compounds is compared to this excellent local effectiveness surprisingly low. In the specified dose range, measured by body weight, mixed adrenal glands and thymus weight, is with 6a, 9a-difluoro-17a, 21-dihydroxy-16a-methyl-pregna- ". -1,4, ll-triene-3,20-dione 17, 21-dipropionate also with the highest Dose no systemic effect detectable; also the 6a, 9a- • »-Difluor ^ l-hydroxy-loaj ^ a-isopropylidendioxy-pregna-l, 4,11- -triene-3,20-dione 21 acetate only shows up in the highest test dose the first signs of systemic activity. This dissociative nature of local and systemic activity is particularly desirable because the latter is viewed as a troublesome side effect in most therapeutic applications.

609886/1215

ciBA-GEiGYAG - 32 -

The compounds of the formula IB characterized above are generally from the corresponding llß-hydroxy -9a-fluorine compounds by the dehydration process according to the invention directly available, provided that the remaining free hydroxyl groups have been removed in a suitable manner, e.g. by esterification to be protected. It should be noted that for adequate protection of both hydroxyl groups in the 17a and 21 positions, it is sufficient if only one of the two hydroxyl groups, any which, by a carboxylic acid having at least 3 carbon atoms, such as Propionic, butyric, valeric or trimethyl acetic acid, is esterified. If compounds of the formula IB which contain free hydroxyl groups are desired, they are made from the corresponding end products, which contain these groups in an esterified or etherified form, by hydrolysis, preferably in that described above Way, received. conversely, free hydroxyl groups can also be added subsequently in a known manner in the compounds obtained esterify, or ketalize the 16a, 17a-diol moiety or acetalize. If you want, you can also go to a the compound obtained, which is saturated in the corresponding position, introduces the 1,2- and / or 6,7-double bond; advantageous the dehydration methods mentioned at the beginning are used for this purpose. If desired, one can use the compounds obtained of the formula IB, in which R, - a hydrogen atom together with of a free hydroxyl group means, in a manner known per se, ' preferably as described above, in corresponding compounds

609 886/1215

convert, in which R, _{Q stands} for two hydrogen atoms, or _{convert to compounds in which R 1n stands} for an optionally hydrated, acetalized or ketalized oxo group. This latter conversion can, if appropriate, as described at the outset, take place with the elimination of a free 17 <x -hydroxyl group.

The compounds of the general formula IB, in which R _{1n stands} for an optionally esterified hydroxyl group together with a hydrogen atom, are advantageously obtained starting from the corresponding compounds of the formula IB in which R _{1n stands} for two hydrogen atoms, by placing them in the 21-position in halogenated in a manner known per se, exchanging the halogen atom, in particular iodine, for an esterified hydroxyl group and possibly releasing it. The 21-halogenation is preferably carried out by the action of elemental iodine in the presence of calcium oxide and, optionally, calcium chloride. The subsequent exchange of the halogen atom introduced by an esterified hydroxyl group, in particular a lower alkanoyloxy group, is preferably done by treatment with a salt of a corresponding acid, in particular by means of an alkali metal salt or a salt with an organic base, for example with a tertiary amine such as tri-lower alkylamine. Potassium and tri-lower alkyl ammonium lower alkanoates, for example acetates, are particularly advantageous for this reaction.

609886/12 15

ciBA-GEiGYAG _ 34 -

The compounds of the general formulas IA and IB are also obtained by adding corresponding compounds in which one or more oxo groups are present in the form of a ketal, enol ether, or enol acylate, known per se Manner, in particular as described above, hydrolyzed.

The compounds of the formula IB in which R _{Q stands} for a free hydroxyl group and R, ~ for a hydrogen atom together with a free hydroxyl group, are also obtained if a corresponding 17α, 20; 20,21-bismethylenedioxypregnane compound is saponified. Preferred conditions here are those of the acid-catalyzed hydrolysis, for example by means of a dilute lower aliphatic carboxylic acid, such as formic or acetic acid, or by means of hydrofluoric acid, optionally in the presence of urea.

The new compounds according to the invention can

depending on the "choice of the method of operation and the starting materials as Mixtures of isomers or racemates. are present. This is especially important: in the case of compounds that are produced in a totally synthetic way became. Such isomer mixtures possibly obtained can, due to the physico-chemical differences of the Components into their individual components in a known manner, for example by chromatography and / or fractionated Crystallization, to be separated. Any racemates obtained are first in a manner known per se with a optically active compound combined, for example esterified with an optically active acid, and the mixture of isomers thus obtained

609886/1215

· "33 ~

is separated as indicated above. The individual components obtained in this way become the individual antipodes in themselves in a known manner, e.g. by hydrolysis.

- · _ The invention also relates to those embodiments of the above method in which one of an on _any: emanating stage as an intermediate product is obtained in-ι loan compound and the missing steps

'carried out, or in which a starting material is formed under the reaction conditions.

The starting materials for the process of the present invention are known or can be used per se be produced in a known manner. It is expedient to use those starting materials which are those specifically mentioned above Contain substituents, and especially those that. to the end products specifically described or highlighted by formula.

The present invention also relates to the production of pharmaceutical preparations and of contraceptive agents for humans and mammals which contain the new pharmacologically active substances of the present invention described above as active substances together with a pharmaceutical carrier material. The carrier used is organic or inorganic substances which are suitable for enteral, for example oral, parenteral or topical administration. For the formation of the same substances come into question that do not react with the new compounds, such as water _ _a gelatin,

6 0 9 8 3 6 ΪΛ 2 15 "

Lactose, starch, magnesium stearate, talc, vegetable oils,

Benzyl alcohol, gum, "polyalkylene glycols, Vaseline, Cho lesterin and other known excipients. The pharmaceutical preparations may be in solid form, eg as tablets, dragees or capsules, or in liquid form as a barren halb.flüssiger solutions, suspensions, emulsions, ointments or creams If necessary, these pharmaceutical preparations are sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers, They can also contain other therapeutically valuable or biologically active substances.

The invention is described in more detail in the following examples, without thereby limiting the scope. ^^ The temperatures, sir.a given in degrees Celsius.

COPY

BATH ORIGINAL

ciBA-GEiGYAG - 37 -

Example 1.

egg stirred under argon solution of 160 mg 9a-fluoro-11ß, 17/3-hydroxy-17a-methyl-androst-4-en-3-one 17-trifluoroacetate in nl of absolute dioxane becomes 0.12 ml of piperidinosulphur trifluoride set. -The reaction mixture is then stirred for 60 minutes at °, on a sodium bicarbonate solution cooled with ice poured and extracted with ethyl acetate. Wash the organic ones neutral with water and dry with sodium sulfate Solutions deliver after evaporation in a water jet vacuum Common amorphous crude product, from which by chromatography on -fächer weight amount of silica gel with hexane-ethyl acetate (4: 1) as The solvent is pure 9α-fluoro-17/3-hydroxy-17α.-methyl-androsta-, ll-dien-3-one 17-trifluoroacetate is obtained which, after crystallization from acetone / hexane, melts at 146-147 °.

s used as starting material, at 158-159 ° melting 9ce-fluorine-11/3-ihydrox5 ^ -17a-methyl-androst-4-en-3-one 17-trifluoroacetate is obtained by selective trifluoroacetylation of 9a-fluoro-11/3 , 17 ß- dihydroxy-17ct-methylndrost-4-en-3-one in dioxane / methylene chloride / pyridine by means of trifluoric anhydride at -70 °.

Example 2 «

ne solution of 7.2 g of 9a-fluoro-17ß-hydroxy-17a-methyl-androsta-4,11-ien-3-one 17-Trifluoroacetate in 150 ml of methanol is treated with a solution η 11 g. Sodium acetate in 9 ml of water is shredded Boiled for 5 1/2 hours in a gonatroo sphere and evaporated in a washer vacuum. Of the

609886/1215 _C OPy

ORIGINAL INSPECTED

ciBA-GEiGYAG - 38 -

The residue is taken up in methylene chloride and water, the organic phase is washed with water, dried and evaporated. Filtration of a solution of the brownish crude product obtained in methylene chloride over 50 g of aluminum oxide (activity III) gives the free 9a-fluoro-17ß-hydroxy-17-methyl- = androsta-4, ll-dien-3-one, F: 181 -182 ° (from acetone / hexane); ia] _D = -4 ° (c = 0.464-, CHCl ₃ ).

Example 3

■ ^ ine solution of 2.0 g of 9a-fluoro-II / 3, ^ a. ^ L-trihydroxy-löa.-methyl- -pregna-1,4-diene-3,20-dione 17,20-dipropionate ( Dexamethasone-17,21-cipropionate) in 30 ml of dioxane is mixed with 1.8 ml of diethylaminosulfur trifluoride at 25 ° in a glass flask under a sticky atomizer and stirred for four hours at 25 °. The reaction mixture is poured onto ice-cold sodium bicarbonate solution, taken up in ethyl acetate, washed neutral, re-extracted, and the organic phase is dried and evaporated in a water-jet vacuum. The residue is dissolved in a small amount of methylene chloride and chromatographed on 30 times the amount by weight of silica gel. By eluting with a mixture of hexane-ethyl acetate (2: 1), 9a-fluoro-17a, 21-dihydroxy-16ct-methyl-pregna-l, 4, ll-triene-3, 20-dione 17, 21-dipropionate, that according to üiiik; ris ": allization from dichloromethane-diethyl ether-hexane melts at 166-168 °; [a] _β = + 22 ° (c = 0.482; CHCl ₃ ).

609886/1215

C13Ä-GEIGYAG - 39 -

Example 4 .

A suspension of 1.35 g of 9a-fluoro-11ß, 17a, 21-trihydroxy-16a-methyl-prepregna-1,4-diene-3,20-dione-21-propionate (dexamethasone-21-propionate) in 20 ml absolute dioxane, 0.4 ml of piperidinosulphur trifluoride is added at room temperature under an argon atmosphere. After 10 minutes, a clear solution is obtained which is stirred for 41/2 hours at room temperature. Work-up as in Example 3 gives pure 9a-fluoro-17a, 21-dihydroxy-16a-methyl-pregna-1 <, 4 _s ll-triene-3,20-dione 21-propionate, which melts after recrystallization from acetone-hexane at 189 ° (decomposition); [ _a ] _D + 26 ° (c - 0.499? GFXl ₃ ).

Example 5 .

A suspension of 3.0 g of 9a-fluoro = II / 3.17a, 21-trihydroxy-16a-methyl-prepregna-1,4-diene-3,20-dione 17,21-ethyl orthopropionate (dexamethasone ethyl orthopropionate) in 30 ml Section. Dioxane is mixed with 3 ml of piperidinosulphur trifluoride at room temperature under an argon atmosphere and stirred. After 10 minutes, a clear solution ₉ results, which is stirred for a further hour. The reaction mixture is poured onto ice-cold sodium carbonate solution, taken up in ethyl acetate and washed neutral. The organic phase is dried and evaporated in a water jet vacuum. The residue is chromate = graphed on 30 times the amount of silica gel with hexane-ethyl acetate (3; T) as the eluent. The resulting 9a-fluoro-17a _s 21-dihydroxy-16ot-methyl-pr agnail _s 4 _s ll-triene-3 ₉ 20-dione 17 _s 21-ethyl orthopropionate melts after Um =. crystallize from Metltrlenclilorid-BiStliylMtlier-Hessan at 175-176 ° + 38 °

8 ° (c = 0.431 CHCl.,)

• 3 y §i Q U Q s a <i I ©

ciBA-GEiGYAG _ 40 -

Example 6.
A solution of 50 mg 9a-fluoro-17a, 21-dihydroxy-

ien-S _} 20-dione 21-propionate in 2 ml of methanol is mixed with a solution of 35 mg of potassium carbonate in 1 ml of water and 1 ml of methanol and stirred for 30 minutes at 5 °. The reaction solution is neutralized with 50% aqueous acetic acid and concentrated in a water jet vacuum. The residue is taken up in ethyl acetate, the solution is washed with water, dried and evaporated. The crude product obtained is purified by chromatography on silica gel using hexane-ethyl acetate (1: 1) as the eluent and the uniform fractions are crystallized from methylene chloride / acetone / hexane. The 9a-fluoro-17a, 21-dihydroxy-16a.-methyl-pregna-1,4, ll-triene-3,20-dione obtained melts at 207-209 °.

Example 7.
A solution of 50 mg 9a-fluoro-17a, 21-dihydrox} ^T - cooled to 0 °

ien-S, 20-dione 17,21-dipropionate in 2 ml A solution of 70 mg of potassium carbonate in 1 ml of water and 1 ml of methanol is added to methanol and the mixture is stirred at 5 ° for 40 minutes The work-up of the reaction product and the subsequent chromatography are carried out analogously to Example 6. The product obtained is in all respects with the 9a-fluoro-17a described in Example 6, 21-dihydroxy-16a-methyl-pregna-1,4, ll-triene-3,20-dione are identical.

609886/1215 COPY

CILAGEIGY AG _ 41 _

Example 8.

A solution of 1.2 g of 9a-fluoro-17a, 21-dihydroxy-16a-methyl-

-pregna-1,4, ll-triene-3,20-dione 17,21-ethyl orthopropionate in 40 ml of methanol is warmed to 45 °, treated with 2.5 ml of 2N-oxalsic acid and stirred for 30 minutes at 45 °. The reaction mixture is cooled quickly, poured onto ice-cold potassium bicarbonate solution, taken up in methylene chloride, washed with water and dried. The organic phase is evaporated and the residue is chromatographed on 20 times the amount of silica gel with hexane-ethyl acetate (1: 1) as the eluent pure, amorphous 9ct-fluoro-17a, 21-dihydroxy- -loa-methyl-pregna-1,4, ll-triene-3,20-dione 17-propionate,. '"' ° [a] _D = -10 ° (c = 0.462', CHCl ₃ ).

Example 9.

A solution of 400 mg of 9oc-fluoro-17a, 21-dihydroxy-16a-methyl-pregna-1,4, ll-triene-3,20-dione-17-propionate in 1.6 ml of pyridine becomes 0 ° at 0 ° , 8 ml of propionic anhydride are added and the mixture is stirred at 0 ° for two hours. 4 g of ice are added to the reaction mixture and the reaction mixture is stirred for a further hour and then extracted with methylene chloride. The extracts are washed successively with hydrochloric acid, a sodium bicarbonate solution and water, dried and evaporated. The residue is chromatographed on a 20-fold amount of silica gel with hexane-ethyl acetate (2: 1). The 9a-fluoro-17a, 21-dihydroxy-16 "-methyl-pregna-1,4, ll-triene-3, 20-dione 17,21-dipropionate obtained melts after recrystallization from metal chloride-diethyl ether-hexane at 166-167 °; fa] _D = + 22 ° (c = 0.441; CHCl)

609886/1215

¹ tC ^ f ORIGINAL INSPECTED

CLBA-GEIGY AG - 42 -

Example 10.

A solution of 2.28 g of 9a-fluoro-II / 3,17a-dihydroxy-16a-methyl-3, 20-dioxo-pregna-1,4-dien-21-al 17-propionate in 25 ml of abs. Dioxane is mixed with 2.0 ml of piperidinosulphur trifluoride at room temperature under a nitrogen atmosphere and stirred for four hours at 25 °. The reaction mixture is poured onto ice-cold sodium bicarbonate solution and taken up in ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried and evaporated in a water jet vacuum. The oily residue is chromatographed sn 30 times the amount of silica gel and eluted with toluene-ethyl acetate (3: 1). The 9a-fluoro-17a-hydroxy-16a-methyl-3,20-dioxo-pregna-1,4, li-triene-21-al 17-propionate obtained melts at 133 after recrystallization from methylene chloride-diethyl ether-hexane -138 °; [cj + 30 ° (c = 0.523 * CHCl ₃ )

Example 11.

A solution, stirred under argon, of 2.0 g of 9a-fluorine-llß, 17a, 21- -trihydroxy-loß-methyl-pregna-l ^ -diene-S ^ O-dione 17-valerate 21-propionate (betamethasone-17-valerate-21-propionate) in 25 ml 1.8 ml of piperidinosulphur trifluoride are added to dioxane. After 211/4 hours at 25 °, the reaction mixture is poured on ice-cold sodium bicarbonate solution and extracted with methylene chloride. The organic phase is washed neutral with water and dried and evaporated in a water jet vacuum. The amorphous residue obtained is chromatographed on silica gel

6Q9886 / 1215

CIBA-GElGY AG _ 43

and eluted with Rexan / ethyl acetate (3: 1). The obtained pure 9α- -Fluoro-17a., 21-dihydroxy-16β-methyl-pregna-1,4, ll-triene ~ 3,20-dione 17-valerate 21-propionate melts after being dissolved once ~ · from methanol / water at 119-120 °.

Example 12.

A solution of 2.5 g of 6 <x, 9a-Difluor-II / 3,17a, 21-trihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione 21-trimethylacetate (flumethasone- -21-trimethylacetate) in 13 ml of abs. 1.2 ml of piperidinosulphur trifluoride are added to pyridine at room temperature under an argon atmosphere and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured onto ice water and extracted twice with ethyl acetate. The organic phase is washed neutral, dried and evaporated in a water jet vacuum. The residue is dissolved in pyridine, applied to a column charged with 70 g of silica gel and washed out with hexane-ethyl acetate (3: 1). The 6a, 9a-difluoro-17a, 21-dihydroxy-.16a-methyl-pregna-1,4, ll-triene-3,20-dione 21-trimethylacetate obtained melts after recrystallization from acetone / ethyl acetate at 250-252 °; [a] _D + 18 ° (c = 0.499; CHCl ₃ )

Example 13.

A suspension of 2.61 g of 6a, 9a-Difluor-liß, 17a, 21-trihydroxy-, 16a-methyl-pregna-1,4-diene-3,20-dione 17,21-dipropionate (flumethasone -17,21-dipropionate) in 50 ml abs. Dioxane is at room temperature

609886/1215

CtBA-GEIGYAG _ 44 -

and 1.9 ml of piperidinoschefel trifluoride are added under a nitrogen atmosphere and the mixture is stirred at room temperature. After about 20 minutes, the whole amount of steroid is dissolved. After a reaction time of 3 hours, the reaction mixture is processed as indicated in Example 3. The 6a, 9a-difluoro-17a, 21-dihydroxy-16a-methyl-pregna-l, 4, ll-triene-3,20-dione 17,21-dipropionate melts after recrystallization from methylene chloride-diethyl ether-hexane at 114- 116 °; [a] _D + (c = 0.672; CHCl ₃ ).

Example 14.

A suspension of 2.33 g of 6a, 9a-difluoro-II / 3,21-dihydroxy-16a, 17a-isopropylidenedioxy-pregna-1,4-diene-3,20-dione 21-acetate in 35 ml of dioxane is passed over of argon and stirring with piperidinosulphur trifluoride (1.5 ml). The starting material dissolves within 7 minutes. After a further 11/2 hours at room temperature, the reaction mixture is poured onto an ice-cold sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts are washed twice with water, dried over sodium sulphate and concentrated in a water-jet vacuum. The oily crude product is purified by chromatography on 50 times the amount by weight of silica gel. First the 11-piperidinosulfinate of the starting material, which melts at 191-194 °, is eluted with hexane-ethyl acetate (3: 1) and then the desired pure 6ct, 9a-difluoro-21-hydrox3 ^T -16a with hexane-ethyl acetate (2: 1) , 17a-isopropylidenedioxy-prepregna-1,4, ll-triene-3,20-dione 21-acetate. The connection is melting

609886/1215

CiSA-GElGY AG

after recrystallization from acetone / hexane with decomposition at 223-225 °; [a] _D = + 47 ° (c = 0.452-, CHCl ₃ ).

609886/121 B.

Claims (1)

Claims . 1. Process for the production of 11,12-unsaturated 9a- -Fluorsteroiden, characterized in that a 9a-fluoro-11ß-hydroxy-steroid with a compound of the formula FoSX, where X is one derived from a secondary amine Amino group means, converts. 2. The method according to claim 1 for the preparation of compounds of the general formula I. (I) where St the remaining, optionally substituted and / or otherwise modified part of the steroid structure, R is an optionally ketalized oxo group, a optionally substituted lower alkylidene radical, an optionally etherified or esterified hydroxyl group together with a hydrogen atom or an optionally substituted lower aliphatic hydrocarbon radical, or a hydrogen atom together with an optionally substituted lower alkyl radical, and R a lower alkylidene radical, an optionally etherified or esterified hydroxyl 609886/121 p group together with a hydrogen atom, a lower alkyl radical together with a hydrogen atom, or in particular means two hydrogen atoms, where instead of one of each of the hydrogen atoms mentioned, the radicals R and R are one χ y 16,17 double bond can be present, characterized in that that compounds of the general formula II are used as starting materials wherein St, R and R have the meanings given above, and, if desired, the products obtained im Within the scope of the end products of the formula I, they are converted into one another in a manner known per se, and / or mixtures of isomers obtained based on the physico-chemical differences between the components, separates them into their individual components and / or if necessary resulting racemates splitting into optical antipodes. 3. The method according to claim 1 or 2, characterized in that one reacts with an aminosulfur trifluoride whose amino group is a di-lower alkylamino or an optionally C-lower alkylated pyrrolidino, piperidino, morpholino or N ¹ -lower alkylpiperazino group. 609886/121 ciBA-GEiGYAG - 48 - 4. The method according to claim 3, characterized in that one with a symmetrically substituted aminosulfur trifluoride, preferably with diethylaminosulfur trifluoride or piperidinosulphur trifluoride. 5. The method according to any one of claims 1-4, characterized in that starting materials are reacted in which one temporarily protects any free carboxyl and / or hydroxyl groups that may be present. 6. The method according to claim 5, characterized in that to _{protect the 17c £}} 21-dihydroxy-20-Qxo group, only any one of the two hydroxyl groups is esterified by a carboxylic acid containing at least 3 carbon atoms. 7. The method according to any one of claims 1 to 6, characterized in that the products obtained are esterified Carboxyl groups and / or esterified hydroxyl groups released by hydrolysis. 8. The method according to any one of claims 1 to 6, characterized in that the products obtained are etherified Releases hydroxyl groups through hydrolysis. 9. A process according to any one of claims 1 to 6 and 8, characterized in that products ₃ raan obtained in the 17 _s 20; 20,21-Eismethylsndiosy moiety to 17a.2I-dihydroxy hydrolysiart -20-oxo-Gruppisrung. 3088S8 / 1 215 10. The method according to any one of claims 1 to 6, characterized characterized in that free hydroxyl groups are oxidized to oxo groups in the products obtained. 11. The method according to any one of claims 1 to 6, characterized in that one obtained 21-unsubstituted 20- -Oxo-pregnane compound halogenated in the 21-position and then exchanges the halogen atom for an esterified hydroxyl group. 12. The method according to any one of claims 1 to 6, characterized in that one obtained in a 21-hydroxy-20-oxo- -pregnane compound the 21-position hydroxyl group in itself eliminated in a known manner. 13. The method according to any one of claims 1 to 12, characterized characterized in that one starts from a compound obtainable as an intermediate at any stage and the missing steps and / or that a starting material is formed under the reaction conditions. 14. 11,12-unsaturated 9a-fluorosteroid compounds. . el 1
9a-fluoro-ZV steroids according to claim 14, characterized by the general "Formula I. S09886 / 121S CLBA-GEIGY AG (D where St represents the remaining, optionally substituted and / or otherwise modified part of the steroid structure, R an optionally ketalized oxo group, an optionally substituted lower alkylidene radical, an optionally etherified or esterified hydroxyl group together with a hydrogen atom or an optionally substituted lower aliphatic hydrocarbon radical, or a hydrogen atom together with an optionally substituted lower alkyl radical, and R a lower alkylidene ^:! radical, an optionally etherified or esterified hydroxyl group together with a hydrogen atom, a lower alkyl radical together with a hydrogen atom, or in particular two hydrogen atoms, where instead of one of the hydrogen atoms mentioned, the radicals R and R are a χ y 16,17 double bond can be present. 1.3, 9a-fluoro-A steroids according to claim 14, characterized by the general formula IA 609886/1215 CIBA-GEiGY AG R, (IA) R-j is the oxo group, a hydrogen atom together with an esterified one or free hydroxyl group, or two hydrogen atoms, R ~ one Hydrogen atom or the methyl group, R ~ a hydrogen atom or together with the oxygen atom an etherified or esterified by a carboxylic acid hydroxyl group, and R, a hydrogen atom or a lower aliphatic hydrocarbon means, or R “and R, together stand for a valence mark, and in the positions 1,2- "and / oderl6,7- each have an additional double bond may be present. 17. 9 <x ~ fluorine- ^. -steroide according to claim 14, characterized by the formula IA given in claim 16, wherein R, an oxo group, R "a hydrogen atom or the methyl radical _s R-a what s he substance atom, a lower alkyl, a cycloalkyl with 5 or 6 ring members or an alkanoyl with 2 to 12 carbon atoms, and R / is a hydrogen atom or the methyl radical and which can also have a double bond in the 1,2-position » 18. 9a-fluoro-Δ steroids according to claim 14, characterized by the formula IA ₉ given in claim 16 wherein R ^ -two hydrogen atoms ₉ one hydrogen atom together with a free one 609886/1215 CiBA-GEIGYAG Hydroxyl group, or an oxo group, R ~ is a hydrogen atom, R ~ is a lower alkanoyl or hydrogen atom, and R is an unsaturated hydrocarbon radical with 1-4 C atoms, in particular the ethynyl radical, and which is also a double bond in 1,2 - and / or especially in the 6,7 position. 19. 9α-ΡΐυοΓ-Δ steroids according to claim 14, characterized by the general formula IB (IB) wherein R ₁ - a hydrogen atom, an α-oriented methyl radical or, if the 1,2-double bond is present, a chlorine atom, R, an oxo group or a hydrogen atom together with an optionally esterified hydroxyl group, R ₇ a hydrogen atom, the methyl radical or a Halogen atom, R ₀ two hydrogen atoms, the methylene radical, one hydrogen atom together with an α- or ß-oriented methyl radical or a α-oriented free hydroxyl group, Rq is a hydrogen atom or an optionally esterified one Hydroxyl group, and 609886/1215 CIBA-GEiGYAG _ 53 - R, _{o is} two hydrogen atoms, an optionally hydrated or acetalized oxo group, or a hydrogen atom together with an optionally esterified or etherified hydroxyl group, and in which a double bond can be present in each of the 1,2- and / or 6,7- positions, and in which the optionally present 16a, 17a-diol grouping by an oxo compound of the formula R ₁₁ -CO-R ₁₂ , in which R- and R ^ independently of one another denote a hydrogen atom, a lower alkyl, phenyl or benzyl radical or together tetramethylene or Form pentamethylene radical, can be ketalized or acetalized. 20. 9a-fluoro-Δ steroid according to claim 14, characterized by the formula IB given in claim 20, wherein R ₁ - a hydrogen atom or, if the 1,2-double bond is present, a chlorine atom, R 1 - an oxo group, R _{7 is} a hydrogen atom, a methyl radical or a fluorine atom, R _{0 is} two hydrogen atoms or a hydrogen atom with an α-hydroxyl group or a β- or, in particular, α-methyl radical, R _Q and R .. are each independently a free or esterified hydroxyl group, and in which the 1 ₅ 2 double bond is preferably present. 21. 9a-fluoro-Δ "steroids according to claim 20 _s in which R ₁ -, R ^ _3, R ₇ and R. ,,. Have the meanings given there, R _{R is} a hydrogen atom to an α-hydroxyl group and R _{Q is} a Hydroxyl group BAD ORlGiNAU CIBA-GElGY AG - 54 _ means, and in which the 1,2-double bond is present, in the form of the corresponding 16,17-ketals. 22. 9a-fluoro-Δ steroid according to claim 21, wherein the ketonic component of the 16,17-ketal is acetone, cyclopentanone, cyclohexanone or acetophenone. 23. 9a- fluoro-Δ steroids according to claim 20, wherein R _1. , R _0, R ₇ and R have the meanings given there, R _{R is} a hydrogen atom together with an α-methyl group and R _{Q is} a hydrogen atom, and in which the 1,2 double bond is present. 24. 9a-fluorine-Δ "steroids according to claim 14, characterized by the formula IB given in Äiis Claim 19, in which R ^ is a hydrogen atom, R ^ is an oxo group, R _{7 is} a hydrogen, chlorine or fluorine atom, R is a methylene group or two hydrogen atoms, Rq is a hydrogen atom or a free or esterified hydroxyl group and R "stands for zx ^ ei hydrogen atoms, and in which a double bond is present in the 1,2- and / or in the 6,7- -position can be. 25. 9 (x-fluoro - ^^^ - steroids according to claim 24, wherein R "a through sine Nlederalkancarbonsäure is esterified hydroxyl group and the other symbols have the meanings given in the claim mentioned 26. A connection according to claim 14 selected from one Group, which consists of the following compounds: 9a-fluoro-17/3-hydroxy-17ct-methyl-androsta-4, ll ~ dien-3-one and its 17- -Trifluoroacetate; 9a-fluoro-17a, 21-dihydroxy ~ 16cx-methyl-pregna-1,4, ll-triene-3,20-dione and its 17-propionate; 21r.propionate; 17, 21-dipropionate and 17.21- -Aetbyl-orthopropionate; 9a-fluoro-17ct-hydroxy-16a-ynethyl-3 ', 20-dioxo-pregna-l, 4, ll-triene- -21-al 17-propionate; 9a-fluoro-17a, 21-dihydroxy-16β-methyl-pregna-1,4, ll-triene-3,20-dione 17-valerate-21-propionate; 6a, 9a-difluoro-17ct, 21-dihydroxy-16a-methylpregna-1,4, ll-triene-3,20-dione in the form of its 21-trimethylacetate and 17,21 ~ dipropionate, and 6a, 9a-difluoro-21-hydroxy-16a, 17a- -isopropylidenedioxy-pregna-1,4, ll-triene-3,20-dione 21-acetate. 27. The new compounds described in Examples 1 to 14. 28. The compounds obtainable according to one of claims 1 to 13, 29. The method according to one of claims 1 to 13, characterized in that one of the claims 14 to 26 mentioned Establishes connections. 609886 / 121S CfBA-GElGYAG - 56 - 30. Pharmaceutical preparations containing one of the in one of the Claims 14 to 26 named compounds. 609886/1215 70.Gt .335